Funds are requested for the purchase of a new transmission electron microscope (TEM) to support NIH- funded research at Washington University Medical School (WUMS). This proposal will support 40+ NIH grant projects of 6 Major Users and 12 Minor Users, all with substantial, previously published EM experience and demonstrable ongoing need for electron microscopy. Planned EM applications include ultrastructural imaging of subcellular pathology involving multiple organ systems and disease models. This acquisition will contribute to the capability of the EM facility for day to day research TEM and to advance the research capability of a growing group of our investigators and will undoubtedly also serve the needs of new investigators recruited during the microscope's lifetime. Specifically, we intend to replace our 20+ year old JEOL 1200 TEM which is rapidly aging and reaching the end of its dependable lifespan with a new generation 120 kV TEM, the JEOL 1400. Not only will this microscope perform all of the tasks our current microscope handles more efficiently and dependably, but its improved capabilities will extend our research in ways not previously possible. Over the last few years investigators at WUMS have sought out our Research Electron Microscopy Facility (directed by Dr. Schmidt, the PI of this shared instrumentation grant) as an important tool in the advance of a variety of biologic problems. By far our most substantial and continuing use has involved 6 major user groups who have used TEM as an essential tool in their research programs and 12 minor users whose use has been more occasional but no less critical to resolving individual experimental issues. Our microscope has been available to WUMS investigators irrespective of department affiliation on a fee-for-service basis and at a subsidized rate to members of our Diabetes Research Training Center which contributes to its upkeep. Installation of the requested microscope within this established EM Facility will assist in user training, protocol development, scheduling and billing under the supervision of a highly experienced technical staff and Director who together will train and assist users. We have seen a burgeoning interest in the use of EM by graduate students and postdoctoral fellows (see Table C3) who have recognized the insight ultrastructure adds to their research. A new microscope will permit the analysis of mitochondria, axons and nerve terminals, myelin structure, and will contribute to the examination of pancreatic dendritic cell and osteoclast function. No other electron microscope at Washington University has the capability to substitute for the microscope we request, either because of its age or oversubscription which limits our ability to perform world-class research. PUBLIC HEALTH RELEVANCE: The rapidly approaching obsolescence of our JEOL 1200 transmission electron microscope resulting in delays in providing ultrastructural analysis to our large user group has interfered with the ability of investigators at Washington University School of Medicine to perform world-class science and slows the analysis of neurodegenerative, cardiac, gastrointestinal, metabolic and bone diseases. There is no doubt that basic scientific discoveries supported by a new generation electron microscope with enhanced capability and dependability will contribute to the understanding of some of the most prevalent scourges of human health and expedite the development and application of novel therapies.